The invention is generally in the field of stimulus responsive hollow particles, and more specifically in the area of delivery of active agents using stimulus responsive hollow particles.
Techniques for drug delivery have evolved over the last few decades from simple techniques such as encapsulation of drug within a gelatin capsule, compression of drug into a table for oral delivery, or injection of a solution or suspension of drug, to the use of carriers which modify the time and/or rate of delivery. In perhaps the earliest embodiments, dosage forms were modified through the use of enteric coatings so that oral delivery could be achieved with greater efficiency, especially for drugs that are labile at low pH. Efficiency of release was improved through the use of polymers such as polylactide-co-glycolide that not only protect the drug from certain conditions, but also extend the period of release from less than an hour to hours to days to weeks, depending on the mode of administration. Further improvements in release patterns and efficiency of encapsulation, particularly of insoluble and/or labile drugs, were achieved through the use of improved methods of encapsulation and the use of polymers that degrade by surface erosion rather than bulk erosion. Targeted release has been achieved by coupling of specific ligands to the surface of the encapsulated drug.
Although these techniques have worked well with some drugs, drugs that are extremely labile or insoluble are not encapsulated with good efficiency, or are not released with desired kinetics. Liposomes and other forms of lamellar capsules were developed at about the same time as polymeric dosage forms for enhanced delivery of drugs. Liposomes have the advantages that they are self-assembling and can encapsulate drugs under physiological conditions. Liposomes, however, have undesirable stability characteristics. Techniques such as crosslinking of liposomes and incorporation of targeting molecules have been used to enhance stability and delivery of drug.
Systems where encapsulated drug is released as a function of pH are described in the prior art, using polymers that disaggregate at one pH and aggregate at another. These systems, however, require synthesis of complex polymers (such diketopiperazines and polyamino acids) and form aggregates with the drug to be delivered, rather than fully and easily encapsulating the drug. Moreover, these systems rely upon degradation of the dosage form for release of the drug.
Accordingly, it would be advantageous to have hollow particles for encapsulating and delivering active agents in response to a stimulus.
The invention is directed to polymeric hollow particles wherein the permeability of the particle changes in response to a change in one or more environmental conditions, such as pH, temperature, light, ionic strength, electric field, magnetic field, solvent composition, etc. The hollow particles are preferably in the nanometer to micrometer size range. The invention is also directed to methods of making and using the responsive hollow particles.
In one embodiment, the shell of the hollow particles is formed from a pH or temperature sensitive polymer. In this embodiment, an important property is the ability to reversibly vary the permeability of the shell forming polymer membrane in response to an external stimulus. This property provides a means to encapsulate and release substances under extremely mild conditions. Loading and release of the substances can be triggered by the external stimulus. For example, the particles can be formed under conditions that result in compressed, or compacted (low permeability) particles. The particles can then be exposed to the stimulus, which causes the particles to expand or otherwise increase their permeability. The active agent can then be introduced into the particles. The stimulus is then removed, or otherwise counteracted, and the particles return to a low permeability state, forming particles that are xe2x80x9cloadedxe2x80x9d with the active agent.
The particles allow for the encapsulation of low and high molecular weight substances, and even of nanoparticles. Examples include therapeutic, prophylactic, and diagnostic agents, as well as other materials such as cosmetics, dyes or pigments, fragrances, and other compounds with industrial significance. The surface optionally can be modified with specific ligands that allow the particles to be directed to a specific target via molecular recognition.
The invention is also directed to methods for delivery of active agents in response to a stimulus supplied at the point of desired delivery. The methods involve the use of a responsive hollow particle encapsulating the active agent. The hollow particle is designed to be responsive to a stimulus that is present at the intended delivery site or that can be supplied to the intended delivery site. For example, a method for delivery of a drug to the small intestine could involve use of a dosage form including hollow particles that are responsive to the higher pH of the small intestine, relative to the stomach. This may be desirable, for example, for delivery of a drug that is rapidly degraded in the low pH of the stomach.